Transcriptional and Nontranscriptional Functions of E2F1 in Response to DNA Damage

Biswas, Anup; Johnson, D. Gale

doi:10.1158/0008-5472.can-11-2196

Cited by 153 publications

(161 citation statements)

References 29 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…Recruits NER factors to sites of UV-induced DNA damage to augment repair activity. 130,131 Upregulates transcription of atg1, lc3, atg5 and dram. Activates autophagy in response to Etoposide.…”

Section: E2f1mentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

View full text Add to dashboard Cite

DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

show abstract

Section: E2f1mentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Upon DNA damage, pVHL was induced, consistent with an increase in E2F1 activity [48]. Even though knock down of E2F1 could reduce pVHL expression upon DNA damage, pVHL, as well as Apaf1, was still up-regulated, suggesting that E2F1 may partially account for activating pVHL under DNA damage stress.…”

Section: Discussionmentioning

confidence: 62%

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

Wang

Zhang

et al. 2013

Biochemical Journal

View full text Add to dashboard Cite

The VHL (von Hippel-Lindau) gene is a well-defined tumour suppressor linked to hereditary cancer syndromes. Although it is well documented that pVHL (von Hippel-Lindau protein) mediates HIF (hypoxia-inducible factor)-1/2α degradation under conditions of normoxia, accounting for a major mechanism of pVHL in tumour suppression, it remains elusive whether other HIF-independent functions contribute to the pVHL tumour suppressive function. In the present study, we found that pVHL is a downstream target of E2F1, which harbours an E2F1-binding site in its promoter. Moreover, pVHL binds to E2F1 in vitro and in vivo, resulting in inhibition of E2F1 transcriptional activity. Mechanistic studies showed that pVHL binding enhances E2F1 deacetylation. Further immunoprecipitation assays indicated that the pVHL interaction diminishes P/CAF [p300/CREB (cAMPresponse-element-binding protein)-binding protein-associated factor] and p300 association with E2F1, but enhances Sirt1 (sirtuin 1) binding to E2F1. In addition, upon DNA damage, pVHL is induced. Knockdown of pVHL sensitizes cells to DNA-damageinduced apoptosis dependent on E2F1, uncovering a role for pVHL in the response to DNA damage. The findings of the present study reveal a novel function of pVHL and demonstrate a negative-feedback loop between pVHL and E2F1, which may shed new light on the explanation of the role of pVHL in tumour suppression.

show abstract

“…Interestingly, E2F1 is also a target of the miR-17B92 cluster, 56 and this may provide an additional conduit for miR-17B92-mediated suppression of Bim induction. E2F1 is only one of eight E2F family members, 57 therefore discerning its involvement in endothelial apoptosis may be complicated by functional redundancy.…”

Section: Foxo3-dependentmentioning

confidence: 99%

Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3

et al. 2014

View full text Add to dashboard Cite

The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim À / À primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17B92 cluster. Bim mRNA levels were also elevated in miR-17B92 þ / À endothelial cells cultured under steady-state conditions, suggesting that miR-17B92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.

show abstract

Transcriptional and Nontranscriptional Functions of E2F1 in Response to DNA Damage

Cited by 153 publications

References 29 publications

Autophagy and genomic integrity

Autophagy and genomic integrity

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3

Contact Info

Product

Resources

About